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\"A memoir of a year in the life of the author while he battled cancer\"-- Provided by publisher.

Minimally invasive approaches to detect residual disease after surgery are needed to identify patients with cancer who are at risk for metastatic relapse. Circulating tumour DNA (ctDNA) holds promise as a biomarker for molecular residual disease and relapse 1 . We evaluated outcomes in 581 patients who had undergone surgery and were evaluable for ctDNA from a randomized phase III trial of adjuvant atezolizumab versus observation in operable urothelial cancer. This trial did not reach its efficacy end point in the intention-to-treat population. Here we show that ctDNA testing at the start of therapy (cycle 1 day 1) identified 214 (37%) patients who were positive for ctDNA and who had poor prognosis (observation arm hazard ratio = 6.3 (95% confidence interval: 4.45–8.92); P  < 0.0001). Notably, patients who were positive for ctDNA had improved disease-free survival and overall survival in the atezolizumab arm versus the observation arm (disease-free survival hazard ratio = 0.58 (95% confidence interval: 0.43–0.79); P  = 0.0024, overall survival hazard ratio = 0.59 (95% confidence interval: 0.41–0.86)). No difference in disease-free survival or overall survival between treatment arms was noted for patients who were negative for ctDNA. The rate of ctDNA clearance at week 6 was higher in the atezolizumab arm (18%) than in the observation arm (4%) ( P  = 0.0204). Transcriptomic analysis of tumours from patients who were positive for ctDNA revealed higher expression levels of cell-cycle and keratin genes. For patients who were positive for ctDNA and who were treated with atezolizumab, non-relapse was associated with immune response signatures and basal–squamous gene features, whereas relapse was associated with angiogenesis and fibroblast TGFβ signatures. These data suggest that adjuvant atezolizumab may be associated with improved outcomes compared with observation in patients who are positive for ctDNA and who are at a high risk of relapse. These findings, if validated in other settings, would shift approaches to postoperative cancer care. The authors report on prospective exploratory analyses of circulating tumour DNA in an urothelial carcinoma immunotherapy clinical trial.

PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov, number NCT02853305. Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

After cystectomy, patients with muscle-invasive bladder cancer were randomly assigned to pembrolizumab or observation for 1 year. The pembrolizumab group had a median disease-free survival twice as long as the observation group.

In a prospective, randomized trial involving patients with urothelial carcinoma who had undergone radical surgery, adjuvant nivolumab was compared with placebo. The median disease-free survival was 20.8 months with nivolumab and 10.8 months with placebo. Treatment-related adverse events of grade 3 or higher were noted in 17.9% of patients in the nivolumab group.

The clinical effect of intravesical instillation of chemotherapy immediately after transurethral resection of bladder tumours (TURBT) has recently been questioned, despite its recommendation in guidelines. Our aim was to compare TURBT alone with immediate post-TURBT intravesical passive diffusion (PD) of mitomycin and immediate pre-TURBT intravesical electromotive drug administration (EMDA) of mitomycin in non-muscle invasive bladder cancer. We did a multicentre, randomised, parallel-group study in patients with primary non-muscle invasive bladder cancer in three centres in Italy between Jan 1, 1994, and Dec 31, 2003. Patients were randomly assigned to receive treatment by means of stratified blocked randomisation across six strata. Patients and physicians giving the interventions were aware of assignment, but it was masked from outcome assessors and data analysts. Patients were randomly assigned to receive TURBT alone, immediate post-TURBT instillation of 40 mg PD mitomycin dissolved in 50 mL sterile water infused over 60 min, or immediate pre-TURBT instillation of 40 mg EMDA mitomycin dissolved in 100 mL sterile water with intravesical 20 mA pulsed electric current for 30 min. Our primary endpoints were recurrence rate and disease-free interval. Analyses were done by intention to treat. Follow-up for our trial is complete. This study is registered with ClinicalTrials.gov, number NCT01149174. 124 patients were randomly assigned to receive TURBT alone, 126 to receive immediate post-TURBT PD mitomycin, and 124 to receive immediate pre-TURBT EMDA mitomycin. 22 patients were excluded from our analyses because they did meet our eligibility criteria after TURBT: 11 had stage pT2 disease and 11 had carcinoma in situ. Median follow-up was 86 months (IQR 57–125). Patients assigned to receive EMDA mitomycin before TURBT had a lower rate of recurrence (44 [38%] of 117) than those assigned to receive PD mitomycin after TURBT (70 [59%] of 119) and TURBT alone (74 [64%] of 116; log-rank p<0·0001). Patients assigned to receive EMDA mitomycin before TURBT also had a higher disease-free interval (52 months, IQR 32–184) than those assigned to receive PD mitomycin after TURBT (16 months, 12–168) and TURBT alone (12 months, 12–37; log-rank p<0·0001). We recorded persistent bladder symptoms after TURBT in 18 (16%) of 116 patients in the TURBT-alone group (duration 3–7 days), 37 (31%) of 119 in the PD mitomycin post-TURBT group (duration 20–30 days), and 24 (21%) of 117 in the EMDA mitomycin pre-TURBT group (duration 7–12 days); haematuria after TURBT in eight (7%) of 116 patients in the TURBT-alone group, 16 (13%) of 119 in the PD mitomycin post-TURBT group, and 11 (9%) of 117 in the EMDA mitomycin pre-TURBT group; and bladder perforation after TURBT in five (4%) of 116 patients in the TURBT-alone group, nine (8%) of 119 in the PD mitomycin post-TURBT group, and seven (6%) of 117 in the EMDA mitomycin pre-TURBT group. Intravesical EMDA mitomycin before TURBT is feasible and safe; moreover, it reduces recurrence rates and enhances the disease-free interval compared with intravesical PD mitomycin after TURBT and TURBT alone. None.

In muscle-invasive bladder cancer, ctDNA-guided atezolizumab led to longer disease-free survival (9.9 vs. 4.8 months), as well as to longer overall survival (32.8 vs. 21.1 months), than placebo among ctDNA-positive patients.

Background: Urothelial bladder cancer (UBC) is characterised by a high risk of recurrence. Patient monitoring is currently based on iterative cystoscopy and on urine cytology with low sensitivity in non-muscle-invasive bladder cancer (NMIBC). Telomerase reverse transcriptase (TERT) is frequently reactivated in UBC by promoter mutations. Methods: We studied whether detection of TERT mutation in urine could be a predictor of UBC recurrence and compared this to cytology/cystoscopy for patient follow-up. A total of 348 patients treated by transurethral bladder resection for UBC were included together with 167 control patients. Results: Overall sensitivity was 80.5% and specificity 89.8%, and was not greatly impacted by inflammation or infection. TERT remaining positive after initial surgery was associated with residual carcinoma in situ . TERT in urine was a reliable and dynamic predictor of recurrence in NMIBC ( P <0.0001). In univariate analysis, TERT positive-status after initial surgery increased risk of recurrence by 5.34-fold ( P =0.0004). TERT positive-status was still associated with recurrence in the subset of patients with negative cystoscopy ( P =0.034). Conclusions: TERT mutations in urine might be helpful for early detection of recurrence in UBC, especially in NMIBC.

The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC ( n  = 834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provide independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations are significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration is associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirms the higher infiltration of class 2b tumors and demonstrates an association between higher immune cell infiltration and lower recurrence rates. Finally, the independent prognostic value of the transcriptomic classes is documented in 1228 validation samples using a single sample classification tool. The classifier provides a framework for biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials. Multiple molecular profiling methods are required to study urothelial non-muscle-invasive bladder cancer (NMIBC) due to its heterogeneity. Here the authors integrate multi-omics data of 834 NMIBC patients, identifying a molecular subgroup associated with multiple alterations and worse outcomes.